Neuronal ABCA7 loss of function and Alzheimer’s disease

项目总结/摘要 MAYO JACKSONVILLE 目前的遗传学研究表明，迟发性阿尔茨海默病（AD）的易感基因位点与 脂质代谢。虽然ATP结合盒转运蛋白A7（ABCA7）基因变异体强烈表达， 与AD风险相关，ABCA 7中的提前终止密码子（PTC）突变显著增加 早发和晚发AD的风险。ABCA7属于ABC转运蛋白家族，调节 脂质和其他脂质相关分子在细胞膜上的分布。因此，探索 ABCA7在脂代谢中的作用为确定脂代谢紊乱的中枢致病途径提供了重要线索。 ad.虽然ABCA 7在脑细胞类型中的神经元中表达最高，但我们的初步研究表明， ABCA7缺乏改变了与线粒体相关的脂质成分， 伴随着人类诱导的皮质类器官和神经元中的突触失调， 多能干细胞（iPSC）。此外，RNA测序分析还发现，与脂肪相关的途径， 线粒体中的酸性β-氧化和细胞膜稳态主要受ABCA 7影响 老鼠大脑的缺陷。由于脂质在很大程度上有助于调节神经元功能，我们 假设ABCA 7功能丧失改变了细胞器之间的脂质代谢，并干扰了细胞内的脂质代谢。 线粒体在神经元中起作用，导致衰老期间的神经变性和突触功能障碍， ad.因此，这项提案的唯一目的是剖析ABCA 7缺乏如何影响脂质代谢， 神经元，并有助于AD相关的表型，包括线粒体失调和突触 功能障碍在目标1中，我们将研究ABCA 7缺乏如何影响脂质代谢、线粒体 功能和AD相关表型使用iPSC衍生的神经元和皮质类器官。在目标2中，我们 使用神经元特异性Abca7敲除小鼠剖析神经元ABCA7在AD相关表型中的作用 有或没有淀粉样病变的模型，伴随单细胞RNA测序。在目标3中，我们 探索ABCA7缺乏对突触的影响，包括线粒体功能和脂质分布， 从常规Abca7敲除小鼠以及神经元特异性Abca7敲除小鼠中分离突触体 有或没有淀粉样病变的小鼠。总的来说，这些研究应该为我们提供新的见解， ABCA 7的功能链通过干扰AD的致病过程的分子机制 神经元脂质稳态

PROJECT SUMMARY/ABSTRACT MAYO CLINIC JACKSONVILLE Current genetic studies indicate that susceptibility loci in late-onset Alzheimer’s disease (AD) are correlated with lipid metabolism. While ATP-binding cassette transporter A7 (ABCA7) gene variants are strongly associated with AD risk, the premature termination codon (PTC) mutations in ABCA7 significantly increases the risk for both early-onset and late-onset AD. ABCA7 belongs to the ABC transporter family regulating distribution of lipids and other lipid-related molecules across cellular membranes. Thus, exploring functions of ABCA7 in lipid metabolism should provide us important clues to determine the central pathogenic pathway for AD. While ABCA7 expression is the highest in neurons among brain cell types, our preliminary study showed that ABCA7 deficiency alters the compositions of mitochondria-related lipids and impairs mitochondria function accompanied with synaptic dysregulation in the cortical organoids and neurons derived from human induced pluripotent stem cells (iPSCs). In addition, RNA-sequencing analysis also found that pathways related to fatty acid β-oxidation in mitochondria and cellular membrane homeostasis are predominantly affected by ABCA7 deficiency in mouse brains. As lipids substantially contribute to the regulation of neuronal functions, we hypothesize that ABCA7 loss of function alters the lipid metabolism among cellular organelles, and disturbs mitochondria functions in neurons, resulting in neurodegeneration and synaptic dysfunction during aging and AD. Therefore, this proposal uniquely aims to dissect how ABCA7 deficiency impacts lipid metabolism in neurons and contributes to AD-related phenotypes including mitochondria dysregulation and synaptic dysfunction. In Aim 1, we will examine how ABCA7 deficiency influences lipid metabolism, mitochondria function, and AD-related phenotypes using iPSC-derived neurons and cortical organoids. In Aim 2, we will dissect roles of neuronal ABCA7 in AD-related phenotypes using neuron specific Abca7 knockout mouse models with or without amyloid pathology, accompanied with single cell-RNA sequencing. In Aim 3, we will explore impacts of ABCA7 deficiency on synapses, including mitochondria functions and lipid profiles, by isolating synaptosomes from conventional Abca7 knockout mice as well as neuron specific Abca7 knockout mice with or without amyloid pathology. Collectively, these studies should provide us new insights for the molecular mechanisms in which ABCA7 floss of function causes the pathogenic processes of AD by disturbing neuronal lipid homeostasis.